Population pharmacokinetics of Ropivacaine and Bupivacaine after loco-regional administration as anesthetic in hip or knee replacement surgery.
Nicolás J (1), Oltra D (2), Navarro-Fontestad C (2), Nicolás N (3), Ramírez F (4), Alós M (5), Casabo VG (2)
(1) Pharmacy Departament, Hospital Son Llàtzer, Spain. (2) Department of Pharmacy and Pharmaceutics, Faculty of Pharmacy, University of Valencia, Spain. (3) Department of Anesthesiology, Hospital General Universitario de Alicante, Spain. (4) Department of Anesthesiology, Hospital General de L´Hospitalet, Spain. (5) Pharmacy Departament, Hospital General de Castellón, Spain.
Objectives: Ropivacaine and Bupivacaine are two local anesthetics commonly used for epidural and regional anesthesia. The joint and simultaneous administration can be beneficial with respect to their separate administration. The aim of this study was to establish the population pharmacokinetics of Ropivacaine (RO) and Bupivacaine (BU) after joint loco-regional administration as anesthetic in hip or knee replacement surgery, and to study the influence of patient covariates on drug disposition.
Methods: A population pharmacokinetic (PK) analysis was performed in NONMEM V using a dataset comprising 32 patients (164 plasmatic concentrations dataset). Demographic and biochemical data were recorded. Ropivacaine (168.75mg) and Bupivacaine (112,5mg) were administered. Venous blood samples were collected to determine Ropivacaine and Bupivacaine concentrations at 1, 4 and 24 hours after administration. The final population model was validated through bootstrapping (n=200).
Results: The PK of Ropivacaine after local administration was described by one compartment model with first order absorption and the PK of Bupivacaine after local administration was described by two compartment model with first order absorption. Interindividual variability (IIV) was included in Ropivacaine clearance CLRO (53%), Bupivacaine clearance CLBU (113%), distribution volume of Ropivacaine VdRO (62%), central distribution volume of Bupivacaine VcBU (4%) Ropivacaine absorption rate constant KARO (0%) and Bupivacaine absorption rate constant KABU (545%). Bioavailability F was fixed to 100%. Residual error was a proportional: 25.8% error model. The FO estimation method was used.
The final population PK parameters were: CLRO=3.51 L/h; CLBU=5.44 L/h; VdRO=65.3 L; VcBU=3.14+0.027*(body weight-70) L; KARO=3.85 h-1; KABU=1.41+0.013*(age-75) h-1; K12BU=46.1 h-1; K21BU=0.353 h-1.
Mean values from the bootstrap analysis were close to the parameter estimate from the original dataset.
Conclusions: A population PK model for Ropivacaine and Bupivacaine, after local administration, has been developed. This model incorporates measure of body weigt to predict Bupivacaine total drug clearance and age to predict Bupivacaine absorption rate constant. Validation of this model with external patients should be performed in order to assess the suitability of further RO-BU therapy.
Acknowledgments: This work is supported in part by Biosim EU grant : LSHB-CT-2004-005137 and Consolider-Ingenio 2010: CSD00C-07-2550.